Rheumatoid arthritis (RA) is characterized by inflammation in the synovial membrane, often leading to joint destruction. HLA DRB1 alleles containing the shared epitope (SE) influence RA susceptibility and severity. TNF and its receptors (TNFR1 and TNFR2) play important roles in RA. Methotrexate (MTX) and the TNFR:Fc protein etanercept are effective treatments for RA. However, etanercept is expensive and is not uniformly efficacious. MTX is less expensive than etanercept, but has more side effects. In a small study that needs confirmation, the presence of the HLA DRB1 SE was shown to predict a favorable response of RA to treatment with a combination of disease modifying drugs. It is not known whether the SE or genetic variations in the TNF and TNFR genes influence clinical responses to etanercept. RA patients, especially those treated with agents to suppress the immune system, have increased susceptibility to infections. Preliminary data suggest that particular Fc receptor alleles influence susceptibility to infections in RA patients, independent of treatment. Serious infections have recently been reported in RA patients treated with etanercept, underscoring the need for identification of patients at high risk for infections. This proposal brings together investigators with expertise in genetics, epidemiology, molecular biology of cytokines and Fc receptors, and clinical trials in RA. We will test the following hypotheses: l). genetic polymorphisms in the TNF or TNFR loci, alone or in conjunction with the HLA DRB1 SE, predict clinical response of RA to MTX or etanercept, and 2). genetic polymorphisms in Fc receptors or TNF-related genes predict infections in patients with RA treated with MTX or etanercept. To address these hypotheses, we will take advantage of a large, well-characterized cohort of 632 patients with early RA enrolled in a clinical trial comparing the efficacy of MTX and etanercept (Immunex Protocol 16.0012). Clinical and response data are available and genomic DNA samples have been obtained, making this an exceptionally useful cohort. We will perform genotyping of HLA DRB1, TNF/LT-alpha, TNFR1, and TNFR2 alleles in all subjects in this trial. Results of genotyping will be correlated with responses to treatment with etanercept or MTX. All subjects will also be genotyped at three biologically relevant SNPs of Fc receptors and associations between FcR (or TNF/LT-alpha, TNFR1, TNFR2) genotypes and infections will be sought. This proposal is directly applicable to RFA: AI-98-006: Hyperaccelerated Award/Mechanisms in Immune Disease Trials and will provide important new information on genetic influences on treatment response and infection in RA.